# Fibroblasts Support the Growth of Brain Metastasis by Rendering Cancer Cells Resistant to Chemotherapy and Inducing Immunosuppression in Tumor Microenvironment

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2024 · $391,874

## Abstract

PROJECT SUMMARY/ABSTRACT
Brain metastasis (BrM) is the most common intracranial tumor in adults. Despite advanced therapies, BrM
remains a major cause of morbidity and mortality in patients with lung cancer. The mechanisms underlying BrM
progression and immune evasion remain poorly understood.
Fibroblasts are abundant in the lung cancers that have metastasized to the brain, but functions of fibroblasts in
BrM are still not known. In our preliminary studies, metastasis-associated fibroblasts (MAFs) promote BrM growth
through a soluble form of placental growth factor (PGF). MAF-derived PGF protect cancer cells from treatment
with tyrosine kinase inhibitors (TKIs) and induce immunosuppressive environment in BrM. Based on these
observations, we propose that MAFs-derived PGF supports BrM growth in two ways: 1) directly by stimulating
the proliferation and chemoresistance of cancer cells; 2) indirectly by inducing an immunosuppressive tumor
microenvironment. This hypothesis will be tested in two specific aims: 1) determine how MAF-derived PGF
directly regulates the proliferation and TKI resistance of cancer cells in BrM. 2) determine how MAF-derived PGF
causes immunosuppression in BrM.
Our studies will establish the importance of MAF-derived PGF in inducing TKI resistance and
immunosuppression in BrM. PGF neutralizing antibodies efficiently penetrate the brain, and already show
promise in treating primary brain tumors, both in preclinical studies and in ongoing clinical trials. Our studies will
provide strong mechanistic rationale and pave the way for therapeutic use of PGF antibodies in treating BrM.

## Key facts

- **NIH application ID:** 10851933
- **Project number:** 5R01CA276273-02
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** Zeng-Jie Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $391,874
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851933

## Citation

> US National Institutes of Health, RePORTER application 10851933, Fibroblasts Support the Growth of Brain Metastasis by Rendering Cancer Cells Resistant to Chemotherapy and Inducing Immunosuppression in Tumor Microenvironment (5R01CA276273-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10851933. Licensed CC0.

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